The present invention relates to azole compounds useful as antifungal therapeutic agents, methods for producing the same and use thereof.
A variety of azole compounds have been reported exhibiting antifungal activity (see, for example, EP0122056A1, EP0332387A1, EP0122693A1 and EP0567982A).
None of these azole compounds, however, is satisfactory as a pharmaceutical agent in terms of its antifungal activity, antifungal spectrum, side effect and in vivo pharmacokinetics.
There has been a demand for a safer compound which exhibits better absorption in vivo and higher antifungal activity as an antifungal therapeutic agent.
The present invention provides
(1) a compound represented by the formula (I): 
xe2x80x83wherein Ar is an optionally substituted phenyl group; R1 and R2, the same or different, are a hydrogen atom or a lower alkyl group, or R1 and R2 may combine together to form a lower alkylene group; R3 is a hydrogen atom or an acyl group; X is a nitrogen atom or a methine group; A is Yxe2x95x90Z (Y and Z, the same or different, are a nitrogen atom or a methine group optionally substituted with a lower alkyl group) or an ethylene group optionally substituted with a lower alkyl group; n is an integer from 0 to 2; and Az is an optionally substituted azolyl group, or a salt thereof,
(2) a process for preparing a compound of the formula (I) as defined in claim 1 or a salt thereof which comprises
(i) reacting a compound represented by the formula (II): 
xe2x80x83wherein the symbols have the same meanings as defined above; or a salt thereof
with a compound represented by the formula (III): 
xe2x80x83wherein the symbols have the same meanings as defined above; or a salt thereof, and, if necessary, followed by an acylation;
(ii) reacting a compound represented by the formula (IV): 
xe2x80x83wherein the symbols have the same meanings as defined above; or a salt thereof
with a compound represented by the formula (Vxe2x80x2): 
xe2x80x83wherein Axe2x80x3 is xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94; the symbols have the same meanings as defined above; or a salt thereof, and, if necessary, followed by an acylation; or
(iii) reducing a compound represented by the formula (Ixe2x80x3) 
xe2x80x83wherein the symbols have the same meanings as defined above; or a salt thereof, and, if necessary, followed by an acylation,
(3) a pharmaceutical composition to be an antifungal preparation containing a compound represented by the above formula (I) or a salt thereof.
Examples of the substituents for xe2x80x9coptionally substituted phenyl groupxe2x80x9d represented by Ar in the formula (I) include halogen atoms (e.g., fluorine, chlorine, bromide and iodine), lower (C1-4) haloalkyl, lower (C1-4) haloalkoxy, lower (C1-4) alkylsulfonyl, lower (C1-4) haloalkylsulfonyl and the like. Preferably, the substituent is halogen atoms (e.g., fluorine, chlorine, bromine and iodine), and more preferably it is fluorine. The number of the substituents is preferably from one to three, more preferably from one to two.
Examples of Ar include halophenyl, lower (C1-4) haloalkylphenyl, lower (C1-4) haloalkoxyphenyl, lower (C1-4) alkylsulfonylphenyl, lower (C1-4) haloalkylsulfonylphenyl and the like.
Examples of the halophenyl groups include 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 2,4,6-trifluoropheny, 4-bromophenyl and the like.
Examples of the lower (C1-4) haloalkylphenyl groups include 4-trifluoromethylphenyl group and the like.
Examples of the lower (C1-4) haloalkoxyphenyl groups include 4-trifluoromethoxyphenyl, 4-(1,1,2,2-tetrafluoro-ethoxy)phenyl, 4-(2,2,2-trifluoroethoxy)phenyl, 4-(2,2,3,3-tetrafluoropropoxy)phenyl, 4-(2,2,3,3,3-pentafluoropropoxy)phenyl and the like.
Examples of the lower (C1-4) alkylsulfonylphenyl groups include 4-methanesulfonylphenyl and the like.
Examples of the lower (C1-4) haloalkylsulfonylphenyl groups include 4-(2,2,2-trifluoroethanesulfonyl)phenyl, 4-(2,2,3,3-tetrafluoropropanesulfonyl)phenyl, 4-(2,2,3,3,3-pentafluoropropanesulfonyl)phenyl and the like.
Specific examples of the phenyl groups of Ar are phenyl groups substituted with one to two halogen atoms such as 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 4-bromophenyl and the like, among which phenyl groups substituted with one or two fluorine atoms such as 4-fluorophenyl, 2-fluorophenyl and 2,4-difluorophenyl are more preferable and 2-fluorophenyl and 2,4-difluorophenyl are most preferable.
Examples of the lower alkyl groups represented by R1 or R2 in the formula (I) include straight or branched C1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, among which methyl is more preferable. It is particularly preferable that both of R1 and R2 are hydrogen atoms or methyl groups, or one of R1 and R2 is a hydrogen atom and the other is a methyl group.
Examples of the lower alkylene groups formed by the combination of R1 and R2 include straight lower (C2-4) alkylene groups such as ethylene, propylene, butylene and the like, among which ethylene is preferred.
Among them, it is preferable that one of R1 and R2 is a hydrogen atom and the other is a C1-4 alkyl group such as a methyl group and the like.
Examples of the acyl groups represented by R3 in the formula (I) include acyl groups derived from organic carboxylic acids such as alkanoyl, preferably C1-7 alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl and heptanoyl), more preferably C1-3 alkanoyl; arylcarbonyl, preferably C7-15 arylcarbonyl (e.g., benzoyl and naphtalenecarbonyl), more preferably C7-11 arylcarbonyl group; alkoxycarbonyl, preferably C2-7 alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonnyl, sec-bu-toxycarbonyl and tert-butoxycarbonyl), more preferably C2-4 alkoxycarbonyl; aryloxycarbonyl, preferably C7-15 aryloxy-carbonyl (e.g., phenoxycarbonyl), more preferably C7-11 aryloxycarbonyl; aralkylcarbonyl group, preferably C8-20 aralkylcarbonyl (e.g., benzylcarbonyl, phenetylcarbonyl, phenylpropylcarbonyl and naphthylethylcarbonyl), more preferably C8-14 aralkylcarbonyl; and the like.
Preferably, the above acyl groups are those being capable of hydrolyzing in vivo. Examples thereof are formyl, acetyl, benzoyl, benzylcarbonyl and the like. Preferred R3 is a hydrogen atom.
X in the general formula (I) is preferably a nitrogen atom.
Examples of the lower alkyl groups for xe2x80x9ca methine group optionally substituted by a lower alkyl groupxe2x80x9d represented by Y or Z when A is Yxe2x95x90Z in the formula (I) include straight or branched C1-4 alkyl groups (methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl), among which methyl is preferred.
Examples for the methine group optionally substituted with a lower alkyl group represented by Y or Z include methine, ethylidyne (xe2x80x94C(CH3)xe2x95x90), propylidyne (xe2x80x94C(CH2CH3)xe2x95x90), butylidyne (xe2x80x94C(CH2CH2CH3)xe2x95x90) and the like, among which methine, ethylidyne and the like are preferable, and methine and the like are more preferable.
It is preferable that one of Y and Z is a nitrogen atom and the other is methine; that both are methine; that both are nitrogen atoms; and one is a nitrogen atom and the other is ethylidyne. It is particularly preferable that one of Y and Z is a nitrogen atom and the other is methine or both of Y and Z are methine.
When A is xe2x80x9can ethylene group optionally substituted with a lower alkyl groupxe2x80x9d in the formula (I), examples of the lower alkyl groups include straight or branched C1-4 alkyl groups (methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl), among which methyl, ethyl and the like are preferable, and methyl and the like are more preferable.
Examples of the ethylene groups optionally substituted with a lower alkyl group represented by A include ethylene, 1-methylethylene, 1,1-dimethylethylene, 1,2-dimethyl-ethylene, 1-ethylethylene, 1,2-diethylethylene and the like, among which ethylene and the like are preferred.
Specific examples of A are xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94Nxe2x95x90C(CH3)xe2x80x94, xe2x80x94C(CH3)xe2x95x90Nxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94 and the like, among which xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94 and the like are preferred.
In the formula (I), the groups represented by 
are preferably 
and the like, more preferably 
and the like, still more preferably 
and the like.
The integer from 0 to 2 represented by n is preferably 0 or 1, more preferably 0.
Examples of the azolyl groups for xe2x80x9can optionally substituted azolyl groupxe2x80x9d represented by Az in the formula (I) include five-membered aromatic heterocyclic groups containing one to four nitrogen atoms as ring-constituent atoms, which may further contain a hetero atom selected from sulfur or oxygen as a ring-constituent atom, such as pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furazanyl, 1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,4-thiadiazolyl and the like.
In particular, the azolyl groups are preferably pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl and the like, more preferably 1H-pyrazol-1-yl, 1H-imidazol-1-yl, 1H-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2-yl, 1H-1,2,4-triazol-1-yl, 4H-1,2,4-triazol-4-yl, 1H-tetrazol-1-yl, 2H-tetrazol-2-yl and the like, and further more preferably 1H-pyrazol-1-yl, 1H-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2-yl, 1H-1,2,4-triazol-1-yl, 1H-tetrazol-1-yl, 2H-tetrazol-2-yl and the like.
Examples of the substituents for xe2x80x9can optionally substituted azolyl groupxe2x80x9d represented by the above Az include hydroxyl group, optionally esterified carboxyl group (e.g., carboxyl, C1-6 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl), nitro group, amino group, acylamino group (e.g., C1-10 alkanoylamino such as acetylamino, propionylamino and butyrylamino), mono-C1-10 or di-C1-10 alkylamino group (e.g., methylamino, dimethylamino, diethylamino and dibutylamino), C1-6 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, pentyl and hexyl), C1-6 alkoxy group (e.g., methoxy, ethoxy and butoxy), halogen atom (e.g., fluorine, chlorine and bromine), C1-6 haloalkyl group (e.g., trifluoromethyl, dichloromethyl, 2,2,2-trifluoroethyl and 2,2,3,3-tetrafluoropropyl), C1-6 haloalkoxy group (e.g., trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, 2,2,3,3,4,4,5,5-octafluoropentoxy and 2-fluoroethoxy), oxo group, thioxo group, mercapto group, C1-6 alkylthio group (e.g., methylthio, ethylthio and butylthio), C1-6 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl and butanesulfonyl), C1-10 alkanoyl group (e.g., acetyl, formyl, propionyl and butylyl), phenyl group, C1-6 alkylphenyl group (e.g., p-tolyl, mesityl and p-cumenyl), C1-6 alkoxyphenyl group (e.g., 4-methoxyphenyl and 4-isopropoxyphenyl), halophenyl group (e.g., 4-chlorophenyl and 4-fluorophenyl, 2,4,-difluorophenyl), C1-6 haloalkylphenyl group [e.g., 4-trifluoromethylphenyl), C1-6 haloalkoxyphenyl group (e.g., 4-trifluoromethoxyphenyl, 4-(2,2,3,3-tetrafluoropropoxy)-phenyl and 4-(1,1,2,2-tetrafluoroethoxy)phenyl] and the like. These substituents may be substituted on the ring-constituent carbon and/or nitrogen atom(s) of the azolyl group and the number of the substituents is preferably one or two.
Specifically, Az are preferably diazolyl, triazolyl and tetrazolyl such as 
and the like, more preferably 
and the like.
A preferred example of the compound (I) is a compound represented by the formula (Ixe2x80x2) 
(wherein Arxe2x80x2 is a monofluorophenyl (e.g., 2-fluorophenyl) or difluorophenyl (e.g., 2,4-difluorophenyl) group; Axe2x80x2 is xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or CH2xe2x80x94CH2xe2x80x94; and Azxe2x80x2 is an azolyl group selected from the group consisting of a diazolyl, triazolyl, tetrazolyl, thiazolyl or oxazolyl which are optionally substituted with one or two substituents selected from the group consisting of an oxo group, a C1-6 alkyl group (e.g., methyl, ethyl, n-propyl, iso-propyl), a C1-6 haloalkyl group (e.g., trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,3,3-tetrafluoropropyl) and a C1-6 haloalkyloxyphenyl group (e.g., 4-trifluoromethoxyphenyl, 4-(2,2,3,3-tetra-fluoropropoxyphenyl, 4-(1,1,2,2-tetrafluoroethoxyphenyl)) or a salt thereof. In the formula (Ixe2x80x2), Axe2x80x2 is preferably xe2x80x94CH2xe2x80x94CH2xe2x80x94, and Azxe2x80x2 is preferably a triazolyl group and a tetrazolyl group.
The compound represented by the formula (I), (Ixe2x80x2) may be used as a salt thereof. Examples of such salts are pharmacologically acceptable salts such as inorganic acid salts (e.g., hydrochloride, hydrobromide, sulfate, nitrate and phosphorate), organic acid salts (e.g., acetate, tartarate, citrate, fumarate, maleate, toluenesulfonate and methanesulfonate). When carboxyl group is included in the formula (I) as a substituent, it may be an alkali methal (sodium, pottasium and the like) salt.
The compounds represented by the formula (I) or a salt thereof (hereinafter abbreviated as the compound of the present invention) have two or more stereoisomers thereof because of having one or more asymmetric carbon atom in their molecule. It should be understood that any of such stereoisomers as well as a mixture thereof is within a scope of the present invention. Among those, when R1 is hydrogen and R2 is methyl, both the carbon atom to which the optionally substituted phenyl group represented by Ar is bonded and the carbon atom to which R2 is bonded are preferred to be in (R)-configuration.
The compound of the present invention can be produced by, for example, reacting a compound represented by the formula (II): 
(wherein the symbols have the same meanings as defined above) or a salt thereof with a compound represented by the formula (III): 
(wherein the symbols have the same meanings as defined above) or a salt thereof. This reaction provides a compound of the present invention in which R3 is a hydrogen atom.
The reaction can be carried out in a solvent which does not inhibit the reaction. Examples of the solvents are water, ketones (e.g., acetone), sulfoxides (e.g., dimethyl sulfoxide), ethers (e.g., diethyl ether, tetrahydrofuran and dioxane), nitrites (e.g., acetonitrile), aromatic hydrocarbons (e.g., benzene, toluene and xylene), halogenated hydrocarbons (e.g., dichloromethane, chloroform and 1,2-dichloroethane), esters (e.g., ethyl acetate), amides (e.g., dimethylformamide, acetamide, dimethylacetamide and l-methyl-2-pyrrolidinone), ureylenes (e.g., 1,3-dimetyl-2-imidazolidinone) and the like. These solvents may be used either singly or as a mixture of two or more solvents in a suitable mixing ratio.
Further, the reaction is preferably carried out in the presence of a base such as alkali metal hydroxides (e.g., lithium hydroxide, potassium hydroxide and sodium hydroxide), alkali metal hydrides (e.g., potassium hydride and sodium hydride), alkali metal carbonates (e.g., lithium carbonate, sodium bicarbonate, cesium carbonate, potassium carbonate and sodium carbonate), organic acid salts (e.g., sodium acetate), alkali metal alcoholates (e.g., sodium methylate, potassium tert-butylate and sodium tert-butylate), tetrabutylammonium fluoride, bis(tri-n-butylstannyl)oxide and the like.
Alternatively, the desired compound can also be prepared by the reaction in the above solvent using a metal salt (e.g., alkali metal salt such as sodium and potassium salt) of the compound (III) instead of the compound (III).
The amount of the base used is usually about 0:01 to at 100 equivalents, preferably about 0.1 to about 50 equivalents per equivalent of the compound of formula (III) or a salt thereof.
The amount of the compound (III) or a salt thereof is about 1 to about 100 equivalents, preferably about 1 to about 50 equivalents per equivalent of the compound of formula (II) or a salt thereof.
The reaction temperature is not especially limited, but usually within the range of about 0 to about 150xc2x0 C., preferably about 10 to about 120xc2x0 C.
The reaction time is usually within the range of about several minutes to tens of hours (e.g., from five minutes to fifty hours).
In another embodiment, the compound of the present invention can also be prepared by, for example, reacting a compound represented by the formula (IV): 
(wherein the symbols have the same meanings as defined above) or a salt thereof
with a compound represented by the formula (Vxe2x80x2): 
(wherein Axe2x80x3 is xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94, the other symbols have the same meanings as defined above) or a salt thereof. The compound of the formula (Vxe2x80x2) may be a compound represented by the formula (Vxe2x80x3): 
(wherein the symbols have the same meanings as defined above) or a salt thereof. This reaction provides a compound of the present invention which A is Yxe2x95x90Z and R3 is hydrogen.
The reaction is usually carried out in a solvent which does not inhibit the reaction. Examples of the solvents are water, ketones (e.g., acetone), sulfoxides (e.g., dimethyl sulfoxide), ethers (e.g., diethyl ether, tetrahydrofuran and dioxane), nitrites (e.g., acetonitrile), aromatic hydrocarbons (e.g., benzene, toluene and xylene), halogenated hydrocarbons (e.g., dichloromethane, chloroform and 1,2-dichloroethane), esters (e.g., ethyl acetate), amides (e.g., dimethylformamide, acetamide, dimethylacetamide and 1-meth-yl-2-pyrrolidinone), ureylenes (e.g., 1,3-dimetyl-2-imidazolidinone) and the like. These solvents may be used either singly or as a mixture of two or more solvents in a suitable mixing ratio.
Further, the reaction is preferably carried out in the presence of a base such as alkali metal hydroxides (e.g., lithium hydroxide, potassium hydroxide, sodium hydroxide), alkali metal hydrides (e.g., potassium hydride and sodium hydride), alkali metal carbonates (e.g., lithium carbonate, sodium bicarbonate, cesium carbonate, potassium carbonate and sodium carbonate), organic acid salts (e.g., sodium acetate), alkali metal alcoholates (e.g., sodium methylate, potassium tert-butylate and sodium tert-butylate), tetrabutylammonium fluoride, bis(tri-n-butylstannyl)oxide and the like.
Alternatively the desired compound can also be prepared by the reaction in the above solvent using a metal salt (e.g., alkali metal salt such as sodium and potassium salt) of the compound (Vxe2x80x2) or (Vxe2x80x3) instead of the compound (Vxe2x80x2) or (Vxe2x80x3).
The amount of the base used is usually about 0.01 to about 100 equivalents, preferably about 0.1 to about 50 equivalents per equivalent of the compound of formula (Vxe2x80x2) or a salt thereof or (Vxe2x80x3) or a salt thereof.
The amount of compound (Vxe2x80x2) or (Vxe2x80x3) or a salt thereof is about 1 to about 100 equivalents, preferably about 1 to about 50 equivalents per equivalent of the compound of formula (IV) or a salt thereof.
The reaction temperature is not especially limited, but usually within the range of about 0 to about 150xc2x0 C., preferably about 10 to about 120xc2x0 C.
The reaction time is usually within the range of about several minutes to tens of hours (e.g., from five minutes to fifty hours).
According to another embodiment, the compound of the present invention can be prepared by, for example, reacting a compound represented by the formula (VI): 
{wherein L is a leaving group [e.g., halogen atom (e.g., chlorine, bromine and iodine) or R4SO3 (wherein R4 is lower (C1-4) alkyl group or optionally substituted phenyl group)] and the other symbols have the same meaning as defined above} or a salt thereof with a compound represented by the formula (III): 
(wherein the symbols have the same meaning as defined above) or a salt thereof. This reaction provides a compound of the formula (I) in which R3 is hydrogen.
Examples of the C1-4 lower alkyl group represented by R4 are methyl, ethyl, propyl, butyl and tert-butyl.
Examples of the optionally substituted phenyl group are the same as those of the optionally substituted phenyl group represented by Ar.
The reaction is usually carried out in a solvent which does not inhibit the reaction. Examples of the solvents are water, ketones (e.g., acetone), sulfoxides (e.g., dimethyl sulfoxide), ethers (e.g., diethyl ether, tetrahydrofuran and dioxane), nitrites (e.g., acetonitrile), aromatic hydrocarbons (e.g., benzene, toluene and xylene), halogenated hydrocarbons (e.g., dichloromethane, chloroform and 1,2-dichloro-ethane), esters (e.g., ethyl acetate), amides (e.g., dimethylformamide, acetamide, dimethylacetamide and l-methyl-2-pyrrolidinone), ureylenes (e.g., 1,3-dimetyl-2-imidazolidinone) and the like. These solvents may be used either singly or as a mixture of two or more solvents in a suitable mixing ratio.
Further, the reaction is preferably carried out in the presence of a base such as alkali metal hydroxides (e.g., lithium hydroxide, potassium hydroxide and sodium hydroxide), alkali metal hydrides (e.g., potassium hydride and sodium hydride), alkali metal carbonates (e.g., lithium carbonate, sodium bicarbonate, cesium carbonate, potassium carbonate and sodium carbonate), organic acid salts (e.g., sodium acetate), alkali metal alcoholates (e.g., sodium methylate, potassium tert-butylate and sodium tertbutylate), tetrabutylammonium fluoride, bis(tri-n-butylstannyl)oxide and the like.
Alternatively the desired compound can be prepared by the reaction in the above solvent using a metal salt (e.g., alkali metal salt such as sodium and potassium salt) of the compound (III) instead of the compound (III).
The amount of the base used is usually within the range of about 2 to about 100 equivalents, preferably about 2 to about 50 equivalents per equivalent of the compound of formula (III) or a salt thereof.
The amount of the compound (III) or a salt thereof is usually within the range of about 1 to about 100 equivalents, preferably about 1 to about 50 equivalents per equivalent of the compound of formula (VI) or a salt thereof.
The reaction temperature is not especially limited, but usually about 0 to about 150xc2x0 C., preferably about 10 to about 120xc2x0 C.
The reaction time is about tens of minutes to tens of hours (e.g., from thirty minutes to fifty hours).
The compound of the present invention wherein A is an ethylene group optionally substituted with a lower alkyl or salt thereof can be prepared by, for example, subjecting to a catalytic reduction a compound of the formula (Ixe2x80x3): 
(wherein the symbols have the same meaning as defined above) or a salt thereof, or the compound of the formula (I) wherein Y and Z are methine groups optionally substituted with lower alkyl (i.e., a compound (Ixe2x80x2xe2x80x3)): 
(wherein Axe2x80x2xe2x80x3 is a vinylene group optionally substituted with lower alkyl group and the other symbols have the same meanings as defined above) or a salt thereof.
The above-mentioned reaction is usually carried out in the presence of a single or mixed solvent(s) such as water and organic solvents which do not inhibit the reaction such as ketones (e.g., acetone and methylethyl ketone), alcohols (e.g., methanol, ethanol, propanol, isopropyl alcohol and butanol), esters (e.g., ethyl acetate), hydrocarbons (e.g., benzene, toluene, hexane and xylene), organic carboxylic acids (e.g., acetic acid and propionic acid) and the like. The reaction is usually carried out in the presence of catalyst. A suitable metal catalyst such as palladium-carbon is used as the catalyst. The reduction reaction is carried out at a pressure from atmospheric pressure up to about 150 kg/cm2 at a temperature from room temperature up to about 100xc2x0 C.
Examples of the salts of the above starting compounds (II), (IV), (VI), (Ixe2x80x3) and (Ixe2x80x2xe2x80x3 ) are the same as those of the compounds (I).
When a compound or a salt thereof of the present invention wherein R3 is a hydrogen atom is obtained in the above reactions, the obtained compound or a salt thereof can be converted into by the conventional method to provide a compound of the formula (I) wherein R3 is an acyl group, by treating it with an appropriate acylating agent of R3L1 [wherein R3 is an aliphatic or aromatic carboxylic acid residue (e.g., acetyl, propionyl, butylyl, ethoxycarbonyl, benzoyl, substituted benzoyl) and L1 is group to be removed (e.g., a halogen atom such as chlorine, bromine and the like, an active ester)] in accordance with the conventional method.
The above-mentioned reaction is usually carried out in the presence or absence of a solvent which does not inhibit the reaction. Examples of such solvents are water, ketones such as acetone, sulfoxides such as dimethyl sulfoxide, ethers such as diethyl ether, tetrahydrofuran and dioxane, nitrites such as acetonitrile, aromatic hydrocarbons such as benzen, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, esters such as ethyl acetate, amides such as dimethylformamide, acetamide, dimethylacetamide, ureylenes such as 1,3-dimethyl-2-imidazolidinone, and the like. Also a base (e.g., dimethylaminopyridine, pyridine, pyrroline and triethylamine) may be added to the reaction system for acceleration of the reaction. The amount of the base used is usually about 1 to about 100 equivalents per equivalent of the compound of formula (I) or a salt thereof.
The compound of the present invention obtained as above can be isolated and purified from the reaction mixture by a known procedure per se such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin layer chromatography and the like.
The compound of the present invention may have at least two stereoisomers as mentioned above. Such a stereoisomer can be separately prepared if desired. For example, a single isomer can be obtained by the above reaction using each single isomer of the starting compounds (II), (IV), (VI), (Ixe2x80x3) and (Ixe2x80x2xe2x80x3) or salts thereof. Alternatively, when the obtained product is a mixture of two or more isomers, they can be separated into each isomer by the conventional separating method such as a method for producing a salt with an optically-active acid (e.g., camphorsulfonic acid and tartaric acid), various types of chromatographies, fractional recrystallization and the like.
The salt of the compound of the present invention can be prepared by a known method per se such as adding the aforesaid inorganic or organic acid to the compound (I).
The starting compound (II) or a salt thereof in the present invention wherein R1 is hydrogen, R2 is methyl, the carbon atom to which Ar is bonded is an (S)-configuration and the carbon atom to which R2 is bonded is an (R)-configuration [i.e., a compound (VII) or a salt thereof] can be prepared, for example, by a method represented by the following reaction scheme: 
(wherein Me is methyl, Et is ethyl, Pr is propyl, Ph is phenyl, (R) and (S) denote the respectively symbolized configurations of the carbon atoms, DMF is dimethylformamide, and the other symbols have the same meanings as defined above).
The starting compound (VIII) in the reaction can be prepared, for example, by a method represented by the following reaction scheme: 
[wherein THP is tetrahydropyranyl group, Ts is p-toluenesulfonyl group, L2 is a halogen atom (e.g., chlorine, bromine, iodine), DMSO is dimethylsulfoxide, and the other symbols have the same meanings as defined above].
The intermediate compound (IX) can be synthesized, for example, by a method represented by the following reaction scheme: 
wherein the symbols have the same meanings as defined above).
The starting compound (IV) in the present invention wherein R1 is a hydrogen atom, R2 is a methyl group, the carbon atom to which Ar is bonded is in an (R)-configuration and the carbon atom to which R2 is bonded is in an (S)-configuration [i.e., a compound (XVIII)]: 
(wherein the symbols have the same meanings as defined above) can be synthesized, for example, by methods described in EP0421210A, EP0548553A or EP0567982A or by a method based thereon.
The starting compound (VI) or a salt thereof in the present invention wherein R1 is a hydrogen atom, R2 is a methyl group, the carbon atom to which Ar is bonded in (S)-configuration, the carbon atom to which R2 is bonded in (R)-configuration, and L is a leaving group represented by R4SO3 (wherein R4 has the same meaning as mentioned above) [i.e., a compound (XIX) or a salt thereof], and the starting compound (II) or a salt thereof in the present invention wherein R1 is a hydrogen atom, R2 is a methyl group, the carbon atom to which Ar is bonded in (S)-configuration and the carbon atom to which R2 is bonded in (R)-configuration [i.e., a compound (VII) or a salt thereof] can be prepared, for example, by a method represented by the following reaction scheme: 
[wherein each of L3, L4, L5 and L6 is a halogen atom (e.g., chlorine, bromine, iodine) and the other symbols have the same meanings as defined above].
The starting compound (XX) or a salt thereof and the starting compound (XXI) or a salt thereof in the above reaction wherein L3 is a chlorine atom [i.e., a compound (XXVI) or a salt thereof] can be each prepared, for example, by a method represented by the following reactions scheme: 
[wherein R5 is a lower alkyl group, L7 is a halogen atom (e.g., chlorine, bromine, iodine) and the other symbols have the same meanings as defined above].
A synthesizing method for a compound (XXXI) or a salt thereof in which Ar is 2,4-difluorophenyl as mentioned in the above reaction scheme is described in Japanese Patent Laid-Open No. HEI 5(1993)-230038. 
(wherein H2/Pd-C denotes a catalytic reduction using palladium-carbon catalyst and the other symbols have the same meanings as defined above).
A compound (XXI) or a salt thereof wherein L3 is a halogen atom except chlorine can be prepared using the corresponding halogenating agent [e.g., (COBr)2, PBr3] instead of (COCl)2 in a similar way to the above reaction.
The starting compounds (V) or a salt thereof in the present invention wherein A is xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94[i.e., compounds (XXXVII), (XXXVIII) and (XXXIX) or salts thereof respectively] can be prepared, for example, by the method represented by the following reaction scheme: 
(wherein the symbols have the same meanings as defined above).
Further, the starting compound (V) or a salt thereof wherein A is xe2x80x94CHxe2x95x90Nxe2x80x94 [i.e., a compound (XXXXIV) or a salt thereof] can be prepared, for example, by a method represented by the reaction scheme: 
(wherein the symbols have the same meanings as defined above).
The starting compounds or synthesized intermediate compounds above-obtained can be isolated and purified from the reaction mixtures by a known procedure per se such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin layer chromatography and the like. Alternatively the reactant mixture itself can be used as a material in the next step without isolation.
The compound of the present invention has low toxicity and exhibits potent antifungal activity with broad antifungal spectrum against, for example, microorganisms of genus Candida (e.g., Candida albicans, Candida utilis, Candida grabrata, etc.), those of genus Histoplasma (e.g., Histoplasma capsulatum, etc.), those of genus Aspergillus (e.g., Aspergillus niger, Aspergillus fumigatus, etc.), those of genus Cryptococcus (e.g., Cryptococcus neoformans, etc.), those of genus Tricophyton (e.g., Trichophyton rubrum, Trichophyton mentagrophytes, etc.), those of genus Microsporum (e.g., Microsporum gypseum, etc.), those of genus Malassezia (e.g., Malassezia furfur, etc.) and the like. Accordingly, it can be used for prevention and treatment of the systemic fungal infection and dermatomycosis (e.g., candidiasis, histoplasmosis, aspergillosis, cryptococcosis, trichophytosis and microsporumosis) of mammals (e.g., human being, domestic animals and fowls) and further atopic dermatitis. Further, the compound of the invention can be used as an antifungal agent for agricultural use.
When the compound of the present invention is administered to a human being, it can be safely administered either orally or parenterally in the form of pharmaceutical compositions such as oral administration preparations (e.g., powders, granules, tablets, capsules), parenteral preparations [e.g., injections and external preparations (e.g., nasal and dermatological ones), suppositories (e.g., rectal and vaginal ones)] and the like in per se or in mixture with suitable pharmacologically-acceptable carriers, fillers or diluents. The content of the compound of the present invention in a whole pharmaceutical composition is usually 5 to 100 wt %, preferably 20 to 100 wt % in an oral drug and 5 to 30 wt % in a parenteral drug.
Those preparations can be manufactured by methods which are known per se and commonly used in the manufacture of pharmaceutical preparations.
For example, the compound of the present invention can be made into an injection such as aqueous injections together with dispersing agents [e.g., Tween 80 (Atlas Powder, U.S.A.), HCO60 (Nikko Chemicals, Japan), carboxymethylcellulose or sodium alginate], preservatives (e.g., methylparaben, propylparaben, benzyl alcohol and chlorobutanol), isotonic agents (e.g., sodium chloride, glycerol, sorbitol and glucose) and the like, or as oily injections by dissolving, suspending or emulsifying in a plant oil (e.g., olive oil, sesame oil, peanut oil, cotton seed oil and corn oil), propylene glycol and the like.
In the manufacture of preparations for oral administration, the compound of the present invention is compression-molded together, for example, with fillers (e.g., lactose, sugar and starch), disintegrating agents (e.g., starch and calcium carbonate), binders (e.g., starch, arabic gum, carboxymethylcellulose, polyvinylpyrrolidone and hydroxypropylcellulose), lubricants (e.g., talc, magnesium stearate and polyethylene glycol 6000) and the like, followed, if necessary, by coating in accordance with a known method per se with an object of taste-masking or of providing the preparation with enteric or sustained release property. Examples of the coating agents are hydroxypropylmethylcellulose, ethylcellulose, hydroxymethycellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (Rohm, West Germany; a copolymer of methacrylic acid with acrylic acid) and pigments such as titanium oxide and red iron oxide.
The compound of the present invention can be also used solid, semisolid or liquid preparations for external use. For example, in the case of solid external preparation, the compound of the present invention is made into the form of powdered compositions as it is or in a mixture with filler (e.g., glucose, mannitol, starch and microcrystalline cellulose), thickeners (e.g., natural gum, cellulose derivatives and acrylic acid polymers) and the like. In the case of semisolid external preparation, aqueous or oily gel preparation or ointment is preferred. In the case of liquid external preparation, the procedures are nearly the same as those in the case of injections to give oily or aqueous suspensions. pH Adjusting agents (e.g., carbonic acid, phosphoric acid, citric acid, hydrochloric acid and sodium hydroxide), antiseptics (e.g., p-hydroxybenzoates, chlorobutanol and benzalkonium chloride) or the like can be added to the above-mentioned solid, semisolid or liquid preparations. More specifically, it can be used for sterilization of disinfection of skin or mucous membrane as an ointment containing, for example, about 0.1 to 100 mg of the compound of the present invention per gram using Vaseline (petroleum jelly) or lanolin as a base material.
The compound of the present invention can be made into oily or aqueous solid, semisolid or liquid suppositories. Examples of the oily base materials used therefor are higher fatty acid glycerides [e.g., cacao butter and Witepsols (Dynamite-Nobel)], medium fatty acids (e.g., Migriols (Dynamite-Nobel)] or plant oil (e.g., sesame oil, soybean oil and cotton seed oil) and the like. Examples of the aqueous base materials are polyethylene glycols, propylene glycols, and those of the aqueous gel base materials are natural gums, cellulose derivatives, vinyl polymers, acrylic acid polymers.
The dose of the compound of the present invention may vary depending upon the state of infection, the route of administration or the like. In the case of orally administrating it to an adult patient (weight: 50 kg) for the therapy of candidiasis, for example, it is about 0.01 to 100 mg/kg/day and, preferably about 0.1 to 50 mg/kg/day, and more preferably about 1 to 20 mg/kg/day.
When the compound of the present invention is used as an agricultural antifungal agent, it may be dissolved or dispersed in a suitable liquid carrier (e.g., solvents), or mixed or absorbed with a suitable solid carrier (e.g., diluents and fillers), followed, if necessary, by addition of an emulsifier, suspending agent, spreader, penetrating agent, moisturizing agent, thickener, stabilizer, etc. to give the preparation a form such as emulsion, hydrating agent, powder, granules and the like. Such preparations can be prepared by known methods per se. The amount of the compound of the present invention is, for example, about 25 to 150 g, preferably about 40 to 80 g per acre of irrigated rice field for prevention of rice blast diseases.
Examples of the above liquid carrier are water, alcohols (e.g., methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol and ethylene glycol), ethers (e.g., dioxane, tetrahydrofran), aliphatic hydrocarbons (e.g., kerosene, lamp oil and fuel oil), aromatic hydrocarbons (e.g., benzene and toluene), haloganated hydrocarbons (e.g., methylene chloride and chloroform), acid amides (e.g., dimethylformamide and dimethylacetamido), esters (e.g., ethyl acetate and butyl acetate), nitrils (e.g., acetonitrile and propionitrile) and the like. They may be used either singly or as a mixture thereof in a suitable mixture ratio.
Examples of the above solid carriers are plant powder (e.g., soybean powder, tobacco powder and wheat flour), mineral powder (e.g., kaolin and bentonite), alumina, sulfur powder, activated charcoal and the like. They may be used either individually or as a mixture thereof in a suitable mixing ratio.